Chaperone-mediated autophagy modulates regulatory T cell differentiation and function

Abstract

Abstract Autophagy has been shown to regulate many key functions of the immune system including important roles in effector and memory T cell maintenance and function. Our group showed that chaperone-mediated autophagy (CMA), a selective type of autophagy that declines with age, plays a key role in T cell activation. In this work, we have analyzed the role of CMA in generation and function of regulatory T cells (Tregs). We found that resting Tregs display high basal CMA activity, which further increases upon Treg activation. We generated Treg specific CMA-deficient mice (Foxp3:Cre-LAMP2A fl/fl) and found that they have significantly reduced body weight due to reduced fat mass. We propose that the CMA status of adipose tissue infiltrating Tregs may have a direct impact on adipose tissue inflammation state. In fact, as the Treg-specific CMA-deficient mice age, we found marked inflammation and reduced survival, suggesting a role for CMA in maintaining Treg self-tolerance under homeostatic conditions. We confirmed that CMA-deficient Tregs have reduced suppressive activity in vivo and have identified the Treg sub-proteome regulated by CMA using comparative quantitative proteomic analysis of control and CMA-deficient Tregs. This has allowed us to identify cellular pathways behind the mechanism by which CMA regulates Treg function. The proteomic analysis hits will help in identifying potential targets of CMA that could be used therapeutically to modulate Treg function, to prevent autoimmunity or boost anti-tumor immune responses. Supported by grants from NIH P01-AG031782 R01-AI113919